Somatic Mutations in the KCNJ5 Gene Raise the Lateralization Index: Implications for the Diagnosis of Primary Aldosteronism by Adrenal Vein Sampling

Background. The mutations that affect the selectivity filter of the KCNJ5 K+ channel can play a role in triggering and/or maintaining aldosterone oversecretion in primary aldosteronism (PA). We therefore hypothesized that these somatic mutations can be associated with an increased aldosterone secretion from the APA, thus translating in raised plasma aldosterone concentrations (PAC) in the ipsilateral adrenal vein. Aim. To investigate if the lateralization index (LI) at adrenal vein sampling (AVS) is higher in the patients with an APA carrying the mutation (KCNJ5mut), as compared to those without the mutation (KCNJ5wt). Methods. Ninety-two consecutive PA patients who underwent AVS and received diagnosis of APA based on the four corners criteria were recruited. Unequivocal information on the presence or absence of the KCNJ5 mutations was available for each patient. The selectivity index (SI) was calculated as ratio between the right or left adrenal vein PCC (PCCside) and the infrarenal IVC PCC and a cutoff of 2.00 was used. The lateralization index (LI) was calculated in the bilaterally selective AVS as the ratio of PAC/PCC at the APA side to PAC/PCC at the contralateral side. We sequenced the KCNJ5 coding region spanning aminoacids 122 to 199, which include the selectivity filer. Results. The overall prevalence rate of KCNJ5 somatic mutations was 34%; G151R, L168R and T158A mutations were found in 19, 10 and 1 APA respectively. The G151E mutation was not found. The KCNJ5mut and KCNJ5wt groups were similar for gender, age, sK+ levels, while PAC and ARR were higher, and PRA lower (all p<0.05) in the KCNJ5 mut group. In the latter group the LI was higher than in the KCNJ5wt group (29.3± 6.7 vs 16.7±3.9, p< 0.02). This was due to a PAC/PCC ratio which was higher in the adrenal vein ipsilateral to the APA side and lower contralaterally in the KCNJ5mut group. Conclusions. These results provide direct in vivo evidence for a higher aldosterone secretion from APA carrying the KCNJ5 mutations, which translates into higher values of the LI, compared to the tumors without such mutations. Hence, the presence of these KCNJ5 mutations can affect the accuracy of the AVS-based diagnosis of the subtype of PA.

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Influence of somatic mutations on the lateralization index of adrenal vein sampling in aldosterone producing adenomas

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-0033-1336699 ◽

2013 ◽

Vol 121 (03) ◽

Author(s):

A Oßwald ◽

E Fischer ◽

M Bidlingmaier ◽

A Pallauf ◽

C Degenhart ◽

...

Keyword(s):

Somatic Mutations ◽

Adrenal Vein ◽

Adrenal Vein Sampling ◽

Lateralization Index

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Lateralization index but not contralateral suppression at adrenal vein sampling predicts improvement in blood pressure after adrenalectomy for primary aldosteronism

Journal of Human Hypertension ◽

10.1038/jhh.2016.92 ◽

2017 ◽

Vol 31 (7) ◽

pp. 444-449 ◽

Cited By ~ 6

Author(s):

M Tagawa ◽

M Ghosn ◽

H Wachtel ◽

D Fraker ◽

R R Townsend ◽

...

Keyword(s):

Blood Pressure ◽

Primary Aldosteronism ◽

Adrenal Vein ◽

Adrenal Vein Sampling ◽

Contralateral Suppression ◽

Lateralization Index

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Effect of Adrenocorticotropic Hormone Stimulation During Simultaneous Bilateral Adrenal Vein Sampling in Primary Aldosteronism

Hormone and Metabolic Research ◽

10.1055/a-1498-6958 ◽

2021 ◽

Vol 53 (06) ◽

pp. 364-370

Author(s):

Wei Liu ◽

Jingjing Zhang ◽

Yaling Yang ◽

Yinxin Jin ◽

Zaizhao Li ◽

...

Keyword(s):

Primary Aldosteronism ◽

Adrenocorticotropic Hormone ◽

Base Excess ◽

Serum Potassium Level ◽

Adrenal Vein ◽

Acth Stimulation ◽

Adrenal Vein Sampling ◽

Before And After ◽

Carbon Dioxide Combining Power ◽

Lateralization Index

AbstractThe aim of the study was to investigate the significance and influence of adrenocorticotropic hormone (ACTH) stimulation in primary aldosteronism (PA) patients with simultaneous bilateral adrenal vein sampling (AVS). All patients diagnosed with PA underwent simultaneous bilateral AVS with ACTH. In 95 patients, the post-ACTH SI significantly increased (p<0.001), and it gradually decreased from t10–t30 after ACTH stimulation (p<0.001). The unsuccessful catheterization decreased after ACTH stimulation. Time points within 20 min after ACTH stimulation were better for sampling, and the selectivity did not increase over longer periods. According to lateralization before and after ACTH stimulation, the patients could be divided into 3 groups (U, unilateral; B, bilateral): U/U , U/B or B/U, and B/B. Compared with the U/U group, in the U/B or B/U and B/B groups, the lateralization index (LI) was lower both at baseline and after ACTH stimulation (p<0.0001), the contralateral index (CLI) was higher after ACTH stimulation (p<0.003), the serum potassium level was higher (p<0.001), and the carbon dioxide combining power (CO2CP) and base excess (BE) levels were lower. In conclusion, in simultaneous bilateral AVS, ACTH stimulation had significant effects on increasing the catheterization selectivity. Lateralization change was observed after stimulation. After ACTH stimulation, fewer patients could be diagnosed with lateralized PA. Patients with consistent lateralized PA showed a more serious phenotype.

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Laterality Diagnosis of Adrenal Vein Sampling for Primary Aldosteronism Using Aldosterone Alone

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.592 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A291-A291

Author(s):

Norio Wada ◽

Shuhei Baba ◽

Hajime Sugawara ◽

Arina Miyoshi ◽

Shinji Obara ◽

...

Keyword(s):

Primary Aldosteronism ◽

Roc Analysis ◽

Vena Cava ◽

Area Under The Curve ◽

Adrenal Vein ◽

Acth Stimulation ◽

Adrenal Vein Sampling ◽

Left And Right ◽

Lateralization Index

Abstract Background: In adrenal vein sampling (AVS) for primary aldosteronism (PA), cortisol concentration is used to determine successful AVS, and laterality diagnosis is performed using a combination of aldosterone and cortisol concentrations. In this study, we examined the comparison with the conventional method when AVS was determined by aldosterone alone. Subjects and methods: We studied the data from 277 patients with PA who underwent AVS in Sapporo City General Hospital from July 2007 to April 2020. The patients with autonomous cortisol production were excluded. Using the blood samples from adrenal veins and inferior vena cava (IVC) after ACTH stimulation, the predicting ability of the left and right ratio of aldosterone concentration (aldosterone ratio, AR) for lateralization Index (LI) was examined by Receiver operating characteristic (ROC) analysis. The predicting abilities of the ratio of aldosterone concentration between adrenal vein and IVC (aldosterone index, AI) and aldosterone concentration for selectivity index (SI) and contralateral ratio (CR) were also examined by ROC analysis. Results: Six samples (0.01%) with SI <5 after ACTH stimulation those were determined unsuccessful AVS. The results of the area under the curve (AUC) in ROC analysis of aldosterone concentration and AI for prediction of SI>5 was 0.998, 0.990, respectively, p=0.39. The optimal cut-off values of aldosterone concentration and AI for prediction successful AVS were 1700 pg/ml (sensitivity 99.5%, specificity 100%), 7.44 (sensitivity 94.0%, specificity 100%), respectively. Seventy-two patients (27.3%) had LI >4 who were diagnosed as unilateral aldosterone excess. AR had 0.94 of AUC for prediction of LR >4. The optimal cut-off value of AR was 3.53 (sensitivity 86.1%, specificity 94.8%). Eighty-two patients (31.1%) had unilateral CR<1. The AUC of aldosterone concentration and AI for prediction of CR<1 was 0.96, 0.98, respectively, p=0.07. The optimal cut-off values of aldosterone concentration and AI were 13600 pg/ml, 42, respectively. The sensitivity and the specificity at the optimal cut-off points of aldosterone concentration and AI were 91.5%, 91.5% and 91.5%, 94.8%, respectively. Conclusions: The determination of successful AVS and unilateral result in AVS can be predicted using aldosterone alone. It was suggested that AR is useful for tentative interpretation in the cases where the results of aldosterone were previously reported and lateralizing diagnosis of the cases with autonomous cortisol production.

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Three Discrete Patterns of Primary Aldosteronism Lateralization in Response to Cosyntropin During Adrenal Vein Sampling

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2019-01182 ◽

2019 ◽

Vol 104 (12) ◽

pp. 5867-5876 ◽

Cited By ~ 11

Author(s):

Taweesak Wannachalee ◽

Lili Zhao ◽

Kazutaka Nanba ◽

Aya T Nanba ◽

James J Shields ◽

...

Keyword(s):

Next Generation Sequencing ◽

Primary Aldosteronism ◽

Time Dependent ◽

Adrenal Vein ◽

Driver Mutations ◽

Adrenal Vein Sampling ◽

Mutation Status ◽

Hormonal Fluctuations ◽

Lateralization Index ◽

Generation Sequencing

Abstract Context Cosyntropin [ACTH (1–24)] stimulation during adrenal vein (AV) sampling (AVS) enhances the confidence in the success of AV cannulation and circumvents intraprocedure hormonal fluctuations. Cosyntropin’s effect on primary aldosteronism (PA) lateralization, however, is controversial. Objectives To define the major patterns of time-dependent lateralization, and their determinants, after cosyntropin stimulation during AVS. Methods We retrospectively studied patients with PA who underwent AVS before, 10, and 20 minutes after cosyntropin stimulation between 2009 and 2018. Unilateral (U) or bilateral (B) PA was determined on the basis of a lateralization index (LI) value ≥4 or <4, respectively. Available adrenal tissue underwent aldosterone synthase–guided next-generation sequencing. Results PA lateralization was concordant between basal and cosyntropin-stimulated AVS in 169 of 222 patients (76%; U/U, n = 110; B/B, n = 59) and discordant in 53 patients (24%; U/B, n = 32; B/U, n = 21). Peripheral and dominant AV aldosterone concentrations and LI were highest in U/U patients and progressively lower across intermediate and B/B groups. LI response to cosyntropin increased in 27% of patients, decreased in 33%, and remained stable in 40%. Baseline aldosterone concentrations predicted the LI pattern across time (P < 0.001). Mutation status was defined in 61 patients. Most patients with KCNJ5 mutations had descending LI, whereas those with ATP1A1 and ATP2B3 mutations had ascending LI after cosyntropin stimulation. Conclusion Patients with severe PA lateralized robustly regardless of cosyntropin use. Cosyntropin stimulation reveals intermediate PA subtypes; its impact on LI varies with baseline aldosterone concentrations and aldosterone-driver mutations.

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